Throughout this application, various publications are referenced and full citations for these publications may be found in the text where they are referenced. The disclosures of these publications are hereby incorporated by reference into this application in order to more fully describe the state of the art as known too the skilled therein as of the date of the invention described and claimed herein.
Beta-elemene is a chemical compound that can be extracted from numerous plants. Curcuma Wenyujin Chen et C. Ling, Curcuma aromatia, and Curcuma longa linn (all belonging to Ziniberaceae) are resources for elemene extraction in China. They grow in tropical areas around the world. In China they are found primarily in Guangdong, Sichuan Fujian, Guangxi and Zhejiang provinces. More than 50 different plants have been found to contain beta-elemene, such as Radix Inulae, Radix Ginseng, E. Wenyujin chen et C. Ling and others.
Beta-elemene can be extracted from the essential oil contained in plants. In China, about 40 different essences were found to contain more than 1% beta-elemene. Higher concentrations are found in the essential oil produced from Magnolia sieboldii, Citrus junos leaves and Aglaia odorata flower and particularly, G. Cymbopogon winterianus Jowitt.
G. Cymbopogon winterianus Jowitt is one of the major plant resources for essential oil production in China. The essential oil contains 1.63-5.21% of beta-elemene and the byproduct of essence extraction i.e. crude product, contains as much as 80% beta-elemene.
Currently China produces more than 2000 tons of oil extracted from the G. Cymbopogon winterianus Jowitt annually. This production is over 50% of the world total, and it is one of the major essential oil exports for China. G. Cymbopogon winterianus Jowitt provides a rich resource from which large quantities of beta-elemene can be extracted economically.
Beta-elemene has the chemical name:
1-methyl-1-vinyl-2,4-diisoprotenyl-cyclohexane.
Beta-elemene is found in elemene in the various extracts, along with gamma and delta elemene, which are chemical isomers of the beta-elemene. The extracts contain other compounds as well and it is very difficult to isolate beta-elemene from these other compounds using routine isolation techniques.
Preparations made from Curcuma Aromatica Salisb (which contains elemene) have been a part of Chinese herbal remedies for centuries. It has been used internally and topically for a wide variety of ailments.
Elemene at various concentrations with other ingredients appears in applications as diverse as a mosquito repellent(see U.S. Pat. No. 5,66,781), burn treatment (see U.S. Pat. Nos. 5,558,914 and 5,384,125) and treatment for Herpes Simplex (see U.S. Pat. No. 5,385,733).
Of particular interest is the anti-tumor characteristics exhibited by elemene.
Yang, H., Wang, X. and Yu, L, Journal articlexe2x80x94NHI database ID# 98048492xe2x80x94xe2x80x9cTHE ANTITUMOR ACTIVITY OF ELEMENE IS ASSOCIATED WITH APOPTOSISxe2x80x9d Chung Hua Chung Liu Tsa Chih;18(3) :169-72 1996, Cancer Institute, Zhejiang Medical university, Hangzhou, China determined that the anti-tumor activity of elemene is associated with cell cycle arrest from S to G2M phase transition and with the induction of apoptosis. They further demonstrated this effect in vitro and in vivo to human and murine tumor cells.
All purity and concentration values in this application are reported by volume. The concentration % in a sample is the volume of beta-elemene divided by the total volume of the sample, multiplied by 100.
Guo,Y T. Journal articlexe2x80x94NIH data base ID# 83285582xe2x80x94xe2x80x9cISOLATION AND IDENTIFICATION OF ELEMENE FROM THE ESSENTIAL OIL OF CURCUMA WENYUJINxe2x80x9d, Chung Yao Tung Pao; 8(3):31 1983)(the present inventors were co-authors of this paper) described the isolation of elemene from Curcuma Wenyujin and described elemene""s anti-neoplastic activities. Beta-elemene in a concentration of 92% was used. The beta-elemene was extracted using chromatography.
Wang J., Zhang H,, and Sun, Y. Clinical trial-Journal articlexe2x80x94NIH data base ID#98048551xe2x80x94PHASE III CLINICAL TRIAL OF ELEMENUM EMULSION IN THE MANAGEMENT OF MALIGNANT PLEURAL AND PERITONEAL EFFUSIONSxe2x80x9d reported the use of elemene emulsion in the management of malignant effusions.
Shi, J. Journal articlexe2x80x94NHI data base ID # 82631581xe2x80x94xe2x80x9cExperimental pharmacological studies on the volatile oil of Wen-E-Zhu (Curcuma Aromatica Salisb): Study on the anti-tumor activity of beta-elemenexe2x80x9d xe2x80x94Zhongyao Tongbao, Luda Inst. Medical and Pharmaceutical Sciences, Luda, P.R.China demonstrated that the beta-elemene component of elemene exhibited marked anti-tumor activity against murine Ehrlich ascites carcinoma and rat ascitic reticulum cell sarcoma. Diarrhea and weight loss were reported as side effects during treatment. The material used contained beta-elemene 65%, gamma and delta-elemene 20%, and impurities 15%. The beta-elemene was extracted by chromatography.
Fu, N. W. Journal articlexe2x80x94NIH data base ID #84282970xe2x80x94xe2x80x9cANTITUMOR EFFECT AND PHARMACOLOGICAL ACTIONS OF BETA-ELEMENE ISOLATED FROM THE RHIZOME OF CURCUMA AROMATICAxe2x80x9d, Chung Yao Pao; 9(2) :35-9 1984 reported on the anti-tumor effect of beta-elemene, one of the monomers comprising the elemene isomer. As in Shi. J article above, the material used contained beta-elemene 65%, gamma and delta-elemene 20%, and impurities 15%.
In December 1993 elemene was designated as a Chinese national Class II new drug. In February 1994 the anti-cancer effect of elemene was confirmed by the health authority of the P.R. of China.
During the 2 year trial of the drug in China, it was determined that elemene has not only the ability to manage malignant chest and abdominal ascites, but also had beneficial effects on brain tumors (neuroglioma), liver and esophageal cancer.
The elemene has apparent anti-cancer activity on mouse Ehrlich Ascites Carcinoma (EAC) and mouse leukemia P388, L1210, ARS and rat YAS etc. From the Chinese phase I, II and III clinical trials, it was proved that the elemene exhibits some control over cancerous chest and abdominal ascites and surface tumors. The total effect rate was about 69%. It should be noted that 27% of the cerebral carcinoma patients reached CR level with a combination of the elemene and local chemotherapy in the expanded clinical trials.
The research conducted demonstrated that the beta-elemene component of elemene had significant anti-tumor characteristics and that the primary mechanism was the induction of apoptosis in the tumor cells.
Previous researchers produced beta-elemene by chromatography, which produced only small quantities of beta-elemene at high cost. The maximum purity attained had been 92%.
In addition, work performed in the Department of Embryology of the Dalian Medical University revealed that beta-elemene is able to pass through the brain-blood barrier (BBB) and thus reach tumors within the brain.
It is an object of the present invention to provide for an anti-cancer drug wherein the active ingredient is beta-elemene.
This invention relates generally to compositions of beta-elemene and method of producing higher concentration than previously possible, produced at reasonable cost using abundant plant sources; pharmaceuticals containing beta-elemene and application of the pharmaceuticals to treat various malignant diseases.
Since indications for the pharmaceutical composition of beta-elemene at the present time are mainly for malignant disorders it is an object of the invention to provide a method for applying the pharmaceutical to treat various malignancies, especially neuroglioma and solid tumors.
Having identified the beta-elemene monomer as a component of elemene with a strong anti-tumor activity, it is a purpose of the present invention to provide for a method to produce it in quantity and with sufficient purity to reduce the side effects from any impurities, and provide a standard dosage. As a result, the governmental requirements for pharmaceuticals with respect to analytical definition and reproducible composition, independent from the variable composition of the starting material from any of several plants can be fulfilled.
A further object of the invention is to provide a beta-elemene composition of high concentration (96.4-97.2%). A composition with highly concentrated effective content and minimum impurities is required in many countries with high pharmaceutical standards which are not usually met by simple extracts since the norms apply to pure substances. Until now it has not been possible to prepare such high concentrations of beta-elemene from the plant sources.
Another advantage of the highly concentrated bete-elemene is the reduced amount that must be dosed to be effective.
An additional advantage of highly concentrated beta-elemene is the further removal of inactive substances. The extensive removal of inactive accompanying substances enhances the safety of the pharmaceutical, since the simpler composition of the active component concentrate facilitates a more precise analytical determination of the main components and detection of potential impurities.
It is a further object of the invention to provide a delivery means for effective levels of the beta-elemene to reach surface and internal tumors.
It is a further object of the invention to provide a low-cost high-volume means of production of beta-elemene.
The present invention is the use and preparation of beta-elemene that is characterized by a purity of more than 96%. The invention involves the preparation methods and the composition of an anti-cancer drug, especially with the preparation methods and the composition of an anti-cancer drug in which the beta-elemene is the effective ingredient.